Molecular Genetic Diagnosis On Clinical Diagnostic Assessments That Demonstrate Correlations In Patients With Autosomal Recessive Inherited Retinal Dystrophies

Importance: Inherited retinal dystrophies(IRDs) are a group of retinal degenerations presentinggenetic and clinical heterogeneities, which have challenged the genetic and clinical diagnosis for IRDs.Genetic evaluations in such patient might help with better clinical assessments and managements.Objective: To determine the genetic lesions with phenotypic correlations in patients with diverse autosomal recessive IRDs using next-generation sequencing(NGS). Design, Setting, and Participants: A cohort of 20 Chinese families affected with autosomal recessive IRDs were recruited with their detailed family history and clinical information collected. To call disease causative mutations in the patients, targeted sequence captureof IRDs-relevant genes using two in-house designed microarrays followed by NGS was applied. Bioinformatics annotation, intrafamilial cosegregation analyses, in silico prediction, and functional analyses were subsequently conducted for the variants identified by NGS.Main Outcomes and Measures: Detailed clinical evaluations, identification of disease causative mutations, and clinical diagnosis.Results: Homozygous and biallelic variants were identified in 11 out of the 20 families(55%)as very likely disease causing mutationsincludinga total of 17 alleles, of which 12 are novel. The 17 alleles identified hereinclude 3 missense, 6 nonsense, 4 frameshift, and 4 splice site mutations. In addition, we found biallelic RP1 mutations in a patient with cone-rod dystrophy(CRD), which was not previously correlated with RP1 mutations. Moreover, the identification of pathogenic mutationsin three families helped to refine their clinical diagnoses. Conclusions and Relevance: In this study, many mutations identified in those known loci for autosomal recessive IRDs are novel to our knowledge. Specific RP1 mutations may correlate with CRD. Genetic evaluations with targeted NGS approach might help with better clinical diagnosis and assessments, and should be recommended for such patients.